Diagnostic ultrasound has become a very successful modality in clinical radiology because ultrasound imaging and measurement can provide noninvasive, real-time cross-sectional images and parameter estimations of soft tissue structures and blood flow without ionizing radiation. The advantages of noninvasive methods of imaging and measurement over invasive methods of imaging and measurement include the following: 1) the patient is not subjected to a general procedure involving penetrating the body nor is the patient subjected to the risks associated with an invasive imaging procedure, such as catherization; 2) where imaging and measurement are necessary to assess a patient's condition, noninvasive imaging and measurement are less dangerous alternatives, particularly when the patient's clinical condition is too unstable to permit an invasive procedure; 3) noninvasive imaging and measurement may better enable treating physicians and surgeons to provide an earlier and more focused method of intervention, thereby leading to a safer avenue and an earlier timetable for stabilization of critically ill patients, and 4) noninvasive imaging and measurement can significantly reduce the cost of clinical examinations.
Currently there are no methods available for direct noninvasive measurement of internal cavity pressure. Noninvasive pressure estimation in the cavities of the heart and in major vessels (e.g., the portal vein) would provide clinicians with a valuable tool for assessing patients with valvular heart disease, congestive heart failure and various vascular diseases. Measurement of cavity pressure is important in determining blood flow in the cardiovascular system. Accurate pressure estimation is a key parameter in assisting minute-to-minute settings for patients in intensive care settings. Such measurements would inform the physician of altered physiologic states caused by disease, especially where pressure has become abnormally high or abnormally low. These pressure measurements may be especially useful in emergency settings.
Some microbubble-based ultrasound contrast agents are particularly well suited for pressure measurements because their substantial compressibility enables the microbubbles to vary significantly in size in response to changes in pressure. Pressure changes in turn affect reflectivity of microbubbles after intravenous injection of a contrast agent. It is known that the diagnostic capabilities of ultrasound imaging can be improved by intravenous injection of ultrasound contrast agents (Ophir, J. and Parker, K. J. Contrast Agents in Diagnostic Ultrasound. Ultrasound Med Biol 15: 319-325, 1989; Goldberg, B. B., Liu, J. B. and Forsberg, F. Ultrasound Contrast Agents: A Review. Ultrasound Med Biol 20: 319-333, 1994). Most contrast agents consist of microbubbles of less than 10 .mu.m in diameter in order to circulate through capillaries (Needleman, L. and Forsberg, F. Contrast Agents in Ultrasound. Ultrasound Quarterly 13: 121-138, 1996). Such microbubbles can significantly enhance the backscatter from blood. Moreover, the nonlinear properties of these microbubbles can be used to create new harmonic and subharmonic imaging modalities (Schrope, B. A., and Newhouse, V. L., Second Harmonic Ultrasound Blood Perfusion Measurement. Ultrasound Med Biol 19: 567-579, 1993; Shi, W. T., Forsberg, F. and Goldberg, B. B. Subharmonic Imaging with Gas-filled Microbubbles, J Acoust Soc Am 101, 3139 (abstract), 1997) for detection of blood flow in small or even capillary blood vessels surrounded by stationary or moving tissue.
Contrast microbubbles are often stabilized with a coating of surfactants or with encapsulating elastic shells. (de Jong, N., Hoff, L., Skotland, T. and Bom, N. Absorption and Scatter of Encapsulated Gas Filled Microspheres: Theoretical Considerations and Some Measurements. Ultrasonics 30: 95-103, 1996). The materials on the bubble surface will greatly influence the response of the contrast microbubbles to hydrostatic pressure changes. De Jong and colleagues investigated the effect of the static ambient pressure on the size change of Albunex.RTM. (Molecular Biosystems Inc., San Diego, Calif.) and Quantison.TM. (Andaris Ltd., Nottingham, UK) microbubbles. (de Jong, N., Ten Cate, F. J., Vletter, W. B. and Roelandt, J. R. T. C. (1993). Quantification of Transpulmonary Echocontrast Effects. Ultrasound Med Biol 19: 279-288; de Jong, N. (1996). Improvements in Ultrasound Contrast Agents. IEEE Eng Med Biol Mag 15: 72-82). Most of the Albunex encapsulated microbubbles shrunk and disappeared due to over-pressure, while the Quantison gas-filled microparticles were insensitive to pressure changes due to their rigid shells.
The reflectivity of microbubble contrast agents at the transmit frequency has been found to vary with the hydrostatic blood pressure. Videodensity variations measured during a cardiac cycle in both the ventricles and especially in the left ventricle indicated a large pressure dependence for microbubbles based on sonicated albumin. (Shapiro, J. S., Reisner, S. A., Lichtenberg, G. S. and Meltzer, R. S. Intravenous Contrast Echocardiography with Use of Sonicated Albumin in Humans: Systolic Disappearance of Left Ventricular Contrast after Transpulmonary Transmission. J Am Coll Cardiol 7: 1603-1607, 1990; de Jong et al. Quantification of Transpulmonary Echocontrast Effects. Ultrasound Med Biol 19: 279-288, 1993). This was further confirmed by Gottlieb et al. in an in vitro model. (Gottlieb, S., Ernst, A. and Meltzer, R. S. Effect of Pressure on Echocardio-graphic Videodensity from Sonicated Albumin: An in vitro Model. J Ultrasound Med 14: 101-108, 1995). The effect of hydrostatic pressure on the acoustic transmittance of an Albunex microbubble suspension was studied by Brayman et al (1996), who found that the acoustic transmittance increased with hydrostatic pressure. (Brayman, A. A., Azadniv, M., Miller, M. W. and Meltzer, R. S. Effect of Static Pressure on Acoustic Transmittance of Albunex Microbubble Suspensions. J Acoust Soc Am 99: 2403-2408, 1996). This effect could be caused by the destruction of many of the microbubbles at a pressure comparable to those produced in the heart. The reflectivity of some other agents such as Levovist.RTM. (Schering A G, Berlin, Germany) was reported to be less sensitive to pressure changes. (Schlief, R. Galactose-based Echo-enhancing agents in Ultrasound Contrast Agents, edit by Barry B. Goldberg, Martin Dunitz Ltd, London. pp 75-82, 1997).
There are many interesting bubble oscillations which span the range of possible frequency emissions from subharmonics (as well as ultraharmonics) through higher harmonics (Lauterborn, W. Numerical Investigation of Nonlinear Oscillations of Gas Bubble in Liquids. J Acoust Soc Am 59: 283-293, 1976). Subharmonic oscillation (or ultraharmonic oscillation) of a free bubble occurs only when the exciting acoustic signal exceeds a certain threshold level (Prosperetti, A. Nonlinear Oscillations of Gas Bubble in Liquids: Transient Solutions and the Connection between Subharmonic Signal and Cavitation, J Acoust Soc Am 57: 810-821, 1975; Prosperetti, A. Application of the Subharmonic Threshold to the Measurement of the Damping of Oscillating Gas Bubbles. J Acoust Soc Am 61: 11-16, 1977; Leighton, T. G., The Acoustic Bubble. Academic Press, London, Great Britain, 1994), while the generation of higher harmonics is a continuous process and occurs to various degree for all levels of excitation. Eller and Flynn estimated the threshold acoustic pressure required for subharmonic generation from a spherical bubble driven by a sinusoidal pressure field. (Eller, A. and Flynn, H. G. Generation of Subharmonics of Order One-Half by Bubble in a Sound Field. J Acoust Soc Am 46: 722-727, 1969). They found that the threshold pressure showed a pronounced minimum for bubbles which are close to twice the size of those resonant with the insonifying field. Neppiras (1968) experimentally studied the subharmonic emission from free gas bubbles subjected to sound field with intensities up to the transient cavitation threshold. (Neppiras, E. A. Subharmonic and Other Low-Frequency Emission from Bubbles in Sound-Irradiated Liquids. J Acoust Soc Am 46: 587-601, 1968). The subharmonic emission of a free gas bubble under two-frequency excitation was measured by Leighton et al (1991) and Phelps and Leighton (1996) for the determination of the bubble size. (Leighton, T. G., Lingard, R. J., Walton, A. J. and Field, J. E. Acoustic Bubble Sizing by Combination of Subharmonic Emission with Imaging Frequency. Ultrasonics 29; 319-323, 1991; Phelps, A. D., and Leighton, T. G. High-Resolution Bubble Sizing through Detection of the Subharmonic Response with a Two-Frequency Excitation Technique. J Acoust Soc Am 99: 1985-1992, 1996).
Microbubble-based agents not only produce helpful enhancement of backscattered signals but also generate significant superharmonics and subharmonics of incident ultrasound waves. The subharmonic of the order 1/2 and ultraharmonic of the order 3/2 were observed in the spectrum of insonated Levovist microbubbles by Schrope et al. (Schrope, B. A., Newhouse, V. L. and Uhlendorf. V. Simulated Capillary Blood Flow Measurement Using a Nonlinear Ultrasonic Contrast Agent. Ultrasonic Imaging 14: 134-158, 1992). Chang et al. acquired a Doppler power spectrum of the subharmonic response of Albunex microbubbles. (Chang, P. H., Shung, K. K., Wu, S. and Levene, H. B. Second Harmonic Imaging and Harmonic Doppler Measurements with Albunex," IEEE Trans Ultrason Ferroelec Freq Contr 42: 1020-1027, 1995). Lotsberg et al. investigated the subharmonic emission of Albunex and found no sharp threshold as expected from theory for free bubbles. (Lotsberg, O., Hovem, J. M. and Aksum, B. Experimental Observation of Subharmonic Oscillations in Infoson Bubbles. J Acoust Soc Am 99: 1366-1369, 1996). Shi et al. investigated the subharmonic response of a surfactant-coated microbubble agent to different transmit ultrasound pulses. (Shi, W. T., Forsberg, F., Gupta, M., Alessandro, J., Wheatley, M. A. and Goldberg, B. B. Subharmonic Response of a New US Contrast Agent. Radiology 205(P): 353 (abstract), 1997). Shankar et al. (1998) found that the ratio of the subharmonic signal scattered from contrast microbubbles to that from soft tissues is greater than the microbubble-to-tissue ratio of the second harmonic signals. (Shankar, P. M., Krishna, P. D. and Newhouse, V. L. Advantages of Subharmonic over Second Harmonic Backscatter for Contrast-to-tissue Echo Enhancement. Ultrasound Med Biol 24: 395-399, 1998).
The most important factor responsible for the use of microbubbles as contrast agents lies in the difference in compressibility between the bubble and the surrounding medium. For a bubble filled with an ideal gas (e.g., air) at atmospheric pressure, the compressibility is nearly 16,000 times greater than the compressibility of water. This allows microbubbles to change substantially in size in response to pressure changes. Changes in the size, in turn, should affect the reflectivity of microbubble contrast agents. This suggests that the intensity of scattered contrast signals may be utilized for the noninvasive detection of pressure changes. The noninvasive estimation of pressures in heart cavities and major vessels would provide clinicians with an invaluable tool for assessing patients with cardiac and vascular diseases, including valvular heart disease, congestive heart failure, portal hypertension and various other vascular diseases. Currently, only the maximum pressure difference across the valves of the heart can be measured non-invasively using Doppler ultrasound and the Bernoulli equation. (Evans, D. H., McDicken, W. N., Skidmore, R. and Woodcock, J. P. Doppler Ultrasound: Physics, Instrumentation and Clinical Applications. John Wiley & Sons, London, UK, 1989).
The dependence of harmonic and sub-harmonic responses on hydrostatic pressure has been studied. (Shi, W. T., Raichlen, J. S., Forsberg, F. and Goldberg, B. B. Effect of Ambient Pressure Change on Subharmonic Response of Microbubbles. J Ultrasound Med, S55: (abstract), 1998; Shi W T, Forsberg F, Raichlen J S, Needleman L, Goldberg B B. Pressure dependence of subharmonic signals from contrast microbubbles. Ultrasound Med Biol 25: 275-283, 1999). In the present invention, results with a galactose-based contrast agent indicate that, over the pressure range of 0-186 mmHg, the subharmonic amplitude of scattered signals decrease by around 10 dB under optimal acoustic settings while the first and second harmonic amplitudes decrease only an average about 2 dB. An excellent correlation (r=0.98) between the subharmonic amplitude and the hydrostatic pressure demonstrates that the subharmonic signal is an excellent indicator for noninvasive detection of pressure changes. The correlation (r=0.98) between the subharmonic amplitude and the hydrostatic pressure was obtained at the growth stage of subharmonic generation.
Based on the measurements made, a technique called SHAPE (Sub-Harmonic-Aided Pressure Estimation) is described in the present invention. SHAPE is a non-invasive, accurate, and direct technique to measure changes in pressure. This technique can be implemented in both penetration and resolution modes in a stand-alone system or in a modified commercial medical ultrasound scanner.
SHAPE allows the clinician to use a non-invasive method of obtaining pulmonary pressures, as well as pressure gradients in the heart. Likewise, SHAPE permits clinicians to follow patients with portal hypertension and associated complications (which may include death) and, therefore, permits earlier intervention to prevent serious complications. Additionally SHAPE enables clinicians to obtain the very important clinical measurement of post-stenotic pressure reductions in patients with claudication (e.g. in the head or kidneys).
In summary SHAPE is a much better approach for pressure measurement than any currently available methods of pressure measurement.